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Cancer Cells Tune the Signaling Pathways to Empower De Novo Synthesis of Nucleotides

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Cancer Cells Tune the Signaling Pathways to Empower De Novo Synthesis of Nucleotides cancers Review Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides 1, 1, 1, 1,2, Elodie Villa y, Eunus S. Ali y , Umakant Sahu y and Issam Ben-Sahra * 1 Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL 60611, USA 2 Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL 60611, USA * Correspondence: [email protected] These authors contributed equally to the work. y Received: 22 April 2019; Accepted: 15 May 2019; Published: 17 May 2019 Abstract: Cancer cells exhibit a dynamic metabolic landscape and require a sufficient supply of nucleotides and other macromolecules to grow and proliferate. To meet the metabolic requirements for cell growth, cancer cells must stimulate de novo nucleotide synthesis to obtain adequate nucleotide pools to support nucleic acid and protein synthesis along with energy preservation, signaling activity, glycosylation mechanisms, and cytoskeletal function. Both oncogenes and tumor suppressors have recently been identified as key molecular determinants for de novo nucleotide synthesis that contribute to the maintenance of homeostasis and the proliferation of cancer cells. Inactivation of tumor suppressors such as TP53 and LKB1 and hyperactivation of the mTOR pathway and of oncogenes such as MYC, RAS, and AKT have been shown to fuel nucleotide synthesis in tumor cells. The molecular mechanisms by which these signaling hubs influence metabolism, especially the metabolic pathways for nucleotide synthesis, continue to emerge. Here, we focus on the current understanding of the molecular mechanisms by which oncogenes and tumor suppressors modulate nucleotide synthesis in cancer cells and, based on these insights, discuss potential strategies to target cancer cell proliferation. Keywords: de novo nucleotide synthesis; oncogenes; tumor suppressors; mTORC1; MYC; RAS; AKT; cancer metabolism; short term and long-term regulation; metabolic vulnerability 1. Introduction Signaling systems allow cells to sense their internal and external surroundings in an integrated manner and generate harmonized responses comprising processes such as growth, proliferation, differentiation, and survival. The development of cancer involves consecutive alterations encompassing signaling, metabolic and genetic modifications that that empower cells to escape self-regulating mechanisms that generally eliminate the survival of abnormally proliferating cells. Although cancer cells are heterogeneous in origin and cell type, most cancer cells share features called hallmarks [1]. Some changes are gain-of-function mutations, causing oncogenes that spur tumor formation; others disable tumor suppressor genes that normally prevent cells from growing improperly or surviving outside their usual niche. Tumorigenesis is generally accompanied by cellular metabolic reprogramming that enables cancer cells to adapt to and sustain the energetic demands required to support growth, proliferation, and survival. A well-described mechanism of metabolic alteration observed in cancer cells is the fermentation of glucose to lactate, called the Warburg effect, where the rate of glycolysis is increased in tumor cells, as compared to that in normal cells [2]. This increase in aerobic glycolysis enables the accumulation of metabolic intermediates required for anabolic reactions, increasing the biomass essential for cancer cell growth and proliferation [3]. Cancers 2019, 11, 688; doi:10.3390/cancers11050688 www.mdpi.com/journal/cancers Cancers 2019, 11, 688 2 of 20 Mechanisms for proper cell division require the preservation of nucleotide pools used for DNA and RNA synthesis. Nucleotides can be produced through salvage pathways, via the recycling of existing nucleosides and nucleobases, or through the de novo synthesis pathways, using amino acids and small molecules to build the purine and pyrimidine rings. Unlike nonproliferating cells, proliferating cells such as immune cells and cancer cells are predisposed to use the de novo nucleotide synthesis pathways [4,5]. The mechanisms explaining the metabolic shift from a normal to a high rate of de novo nucleotide synthesis in cancer cells involve coordinated inputs from metabolic and signaling pathways [6]. De novo biosynthesis of both purines and pyrimidines has been observed to be altered in cancer and requires the generation of 5-phosphoribose-1-pyrophosphate (PRPP), the activated form of ribose derived from ribose 5-phosphate, which is produced through the oxidative and nonoxidative arms of the pentose phosphate pathway (PPP) parallel to glycolysis. The pyrimidine ring is first assembled from glutamine, bicarbonate, and aspartate and is then attached to PRPP through six reactions. The first three reactions in the de novo pyrimidine synthesis pathway are catalyzed by one cytosolic tricatalytic enzyme called carbamoyl phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), which produces dihydroorotate. Then, dihydroorotate enters mitochondria, where it is oxidized to orotate by dihydroorotate dehydrogenase (DHODH). UMP synthase (UMPS) converts orotate through two catalytic reactions into uridine monophosphate (UMP) (Figure1A). Purine synthesis differs from pyrimidine synthesis in that all reactions occur in the cytosol, and the purine ring is directly built onto the activated ribose, PRPP. The purine ring is synthesized from various substrates, including glutamine, glycine, bicarbonate, and N10-formyl-tetrahydrofolate (THF). After a 10-step reaction, inosine monophosphate (IMP) is produced and converted into guanosine monophosphate (GMP) (via the enzymes inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate synthetase (GMPS)) or adenosine monophosphate (AMP) (via metabolic reactions involving adenylosuccinate synthase (ADSS) and adenylosuccinate lyase (ADSL)) (Figure1B). Once formed, the ribonucleoside triphosphates (NTPs) produced de novo can be utilized for RNA synthesis. However, DNA synthesis requires the cytoplasmic reduction of NTPs to deoxy-NTPs catalyzed by the NAPDH-dependent enzyme ribonucleotide reductase (RNR). Nitrogen and carbon that feed de novo nucleotide synthesis are provided by glutamine, aspartate and several glucose-derived metabolites originating from the PPP, the serine/glycine pathway, and one-carbon metabolism [4] (Figure1). It is well recognized that cancer cells rewire their metabolism to enhance de novo nucleotide synthesis in order to grow and proliferate; however, the molecular events by which oncogenes or tumor suppressors modulate these metabolic pathways are not fully elucidated. Here, we systematically review the literature defining the influence of signaling pathways on nucleotide metabolism by first focusing on the short-term molecular features involving posttranslational modifications, then on the long-term processes comprising transcriptional mechanisms and finally on the reemergence of nucleotide metabolism as a new targetable weakness for cancer therapy. Cancers 2019, 11, 688 3 of 20 Cancers 2019, 11, x FOR PEER REVIEW 3 of 20 FigureFigure 1. 1.The Thede de novonovo pyrimidinepyrimidine andand purinepurine synthesis pathways. (A (A) )Schematic Schematic of of the the de de novo novo pyrimidinepyrimidine synthesis synthesis pathway. pathway. Pyrimidine Pyrimidine synthesis synthesis enzymes: enzymes: CAD: Carbamoyl-Phosphate CAD: Carbamoyl-Phosphate Synthetase 2, AspartateSynthetase Transcarbamylase, 2, Aspartate Transcarbamylase, And Dihydroorotase; And DHODH: Dihydroorotase; Dihydroorotate DHODH: Dehydrogenase; Dihydroorotate UMPS: UridineDehydrogenase; Monophosphate UMPS: Synthetase. Uridine Monophosphate (B) Schematic Synthetase. of the de novo (B) Schematic and purine of salvage the de novo pathways. and purine Purine synthesissalvage enzymes:pathways. PPAT: Purine phosphoribosyl synthesis pyrophosphateenzymes: PPAT: amidotransferase; phosphoribosyl GART: pyrophosphate Glycinamide Ribonucleotideamidotransferase; Transformylase; GART: PFAS:Glycinamide Phosphoribosylformylglycinamidine Ribonucleotide Transformylase; Synthase; PFAS: PAICS: PhosphoribosylaminoimidazolePhosphoribosylformylglycinamidine Carboxylase Synthase; And PAIC Phosphoribosylamino-imidazolesuccinocarboxamideS: Phosphoribosylaminoimidazole Carboxylase Synthase;And Phosphoribosylamino-imidazole ADSL: Adenylosuccinate Lyase;succinocarboxamide ATIC: 5-Aminoimidazole-4-Carboxamide Synthase; ADSL: Adenylosuccinate Ribonucleotide Lyase; ATIC: 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase; IMPDH: Inosine Formyltransferase; IMPDH: Inosine Monophosphate Dehydrogenase; GMPS: Guanine Monophosphate Monophosphate Dehydrogenase; GMPS: Guanine Monophosphate Synthase ; ADSS: Synthase; ADSS: Adenylosuccinate Synthase; HPRT: hypoxanthine phosphoribosyltransferase; APRT: Adenylosuccinate Synthase ; HPRT: hypoxanthine phosphoribosyltransferase; APRT: adenine adenine phosphoribosyltransferase. phosphoribosyltransferase. Cancers 2019, 11, 688 4 of 20 2. Acute Regulation of Nucleotide Synthesis by Oncogenes and Tumor Suppressors Altered expression and activity of metabolic enzymes, including enzymes involved in nucleotide synthesis, are regulated by oncogenes and tumor suppressor genes [7]. To examine the mechanism triggering the alteration of nucleotide synthesis characteristically observed in cancer cells, a better understanding of the acute and direct molecular regulation of nucleotide synthesis pathways by signaling systems is critical to identify the initial metabolic events for
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